Translational Upregulation of an Individual p21Cip1 Transcript Variant by GCN2 Regulates Cell Proliferation and Survival under Nutrient Stress.

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Citation

Lehman SL, Cerniglia GJ, Johannes GJ, Ye J, Ryeom S, Koumenis C

Translational Upregulation of an Individual p21Cip1 Transcript Variant by GCN2 Regulates Cell Proliferation and Survival under Nutrient Stress.

PLoS Genet. 2015 Jun 23;11(6):e1005212. doi: 10.1371/journal.pgen.1005212. eCollection 2015 Jun.

PubMed ID
26102367 [ View in PubMed
]
Abstract

Multiple transcripts encode for the cell cycle inhibitor p21(Cip1). These transcripts produce identical proteins but differ in their 5' untranslated regions (UTRs). Although several stresses that induce p21 have been characterized, the mechanisms regulating the individual transcript variants and their functional significance are unknown. Here we demonstrate through (35)S labeling, luciferase reporter assays, and polysome transcript profiling that activation of the Integrated Stress Response (ISR) kinase GCN2 selectively upregulates the translation of a p21 transcript variant containing 5' upstream open reading frames (uORFs) through phosphorylation of the eukaryotic translation initiation factor eIF2alpha. Mutational analysis reveals that the uORFs suppress translation under basal conditions, but promote translation under stress. Functionally, ablation of p21 ameliorates G1/S arrest and reduces cell survival in response to GCN2 activation. These findings uncover a novel mechanism of p21 post-transcriptional regulation, offer functional significance for the existence of multiple p21 transcripts, and support a key role for GCN2 in regulating the cell cycle under stress.

DrugBank Data that Cites this Article

Polypeptides
NameUniProt ID
eIF-2-alpha kinase GCN2Q9P2K8Details